Protective Role of Spermidine in Colitis and Colon Carcinogenesis.

Gastroenterology

Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee; Program in Cancer Biolog Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee. Electronic address:

Published: March 2022

AI Article Synopsis

  • Inflammatory bowel disease is on the rise globally and can lead to a type of cancer known as colitis-associated carcinoma (CAC), prompting the need for new treatment options.
  • Researchers investigated the role of spermine oxidase (SMOX) and spermidine (Spd) in regulating colitis and carcinogenesis using mouse models and human tissue analysis.
  • Findings showed that decreased SMOX levels are linked to worse colitis and cancer outcomes, while Spd treatment improved conditions such as inflammation and altered microbiome profiles, suggesting its potential as a therapy for colitis and prevention of colon cancer.

Article Abstract

Background & Aims: Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis.

Methods: SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed.

Results: SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox mice and was reversed with Spd.

Conclusions: Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8881368PMC
http://dx.doi.org/10.1053/j.gastro.2021.11.005DOI Listing

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